Current cancer therapies rely heavily on radiation and DNA damaging agents to induce both cytotoxic DNA changes and programmed cell death (Neidle S, Thurston D E. Chemical approaches to the discovery and development of cancer therapies. Nat Rev Cancer 2005; 5: 285-96). Cytotoxic DNA damages include bulky lesions, inter-strand crosslinks, double-strand breaks, interruption of transcription, replication, and chromosome segregation (Friedberg E C. DNA damage and repair. Nature 2003; 421: 436-40.). These lesions interfere with DNA metabolic processes and inhibit normal cell and tumor growth.
Among the DNA-targeted chemotherapeutic agents is temozolomide (TMZ, 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]tetrazine-8-carboxamide), which has been widely utilized in cancer therapies (Stevens M F, Hickman J A, Langdon S P, et al. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 1987; 47: 5846-52.). The drug easily penetrates the blood-brain barrier making it particularly useful in treating malignant brain tumors (Newlands E S, Stevens M F, Wedge S R, Wheelhouse R T, Brock C. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 1997; 23: 35-61.). It has shown promising antitumor activity in recent clinical trials (Taliansky-Aronov A, Bokstein F, Lavon I, Siegal T. Temozolomide treatment for newly diagnosed anaplastic oligodendrogliomas: a clinical efficacy trial. J Neurooncol 2006; 79: 153-7; Trudeau M E, Crump M, Charpentier D, et al. Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG). Ann Oncol 2006; 17: 952-6; Hegi M E, Diserens A C, Godard S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 2004; 10: 1871-4; Lanzetta G, Campanella C, Rozzi A, et al. Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Anticancer Res 2003; 23: 5159-64). However, drug resistance remains a critical consequence, often causing treatment failure in clinical use (Mason W P, Cairncross J G. Drug Insight: temozolomide as a treatment for malignant glioma—impact of a recent trial. Nat Clin Pract Neurol 2005; 1: 88-95). A major resistance factor is the presence of elaborate mechanisms of DNA repair (Liu L, Gerson S L. Targeted modulation of MGMT: clinical implications. Clin Cancer Res 2006; 12: 328-31). This resistance is based on the fact that TMZ reacts with DNA forming O6-methylguanine (O6mG), 7-methylguanine (N7mG), and 3-methyladenine (N3mA) DNA adducts that are repaired by three major mechanisms.
The O6mG DNA adduct is a cytotoxic and genotoxic lesion mainly repaired by O6-methylguanine DNA-methyltransferase (MGMT) (Gerson S L. MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 2004; 4: 296-307). Cell death from O6mG adducts is also promoted by mismatch repair (MMR) (Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem 1996; 65: 101-33). Deficiency in MMR is associated with pronounced resistance to TMZ (Caporali S, Falcinelli S, Starace G, et al. DNA damage induced by temozolomide signals to both ATM and ATR: role of the mismatch repair system. Mol Pharmacol 2004; 66: 478-91). Meanwhile, N7mG, the dominant lesion formed by TMZ, and N3mA DNA adducts are removed by the base excision repair (BER) pathway (David S S, Williams S D. Chemistry of Glycosylases and Endonucleases Involved in Base-Excision Repair. Chem. Rev 1998; 98: 1221-62; Fromme J C, Verdine G L. Base excision repair. Adv Protein Chem 2004; 69: 1-41; Barnes D E, Lindahl T. Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu Rev Genet 2004; 38: 445-76). Efficient BER minimizes the impact of these lesions in normal and tumor cells.